SUMMARY ? CORE D The Drug Discovery Core will be a resource providing support for individual investigators in Projects 1-3 through a state-of-the-art, rational-design drug discovery program for early preclinical design of putative antiinflammatory and anti-aggregation agents. The Core already catalogs almost 2500 compounds in two libraries, and another library is under construction. After an initial round of screening in biological assays (Projects 1 and 3), the Core will use the resulting data in previously developed ?training? algorithms (nonlinear QSAR based) for in silico molding of the key structural elements that will not be, at this point, biased toward any known identity or structure. In parallel, the Core will use its extant computational tools to design compounds with structural elements known or predicted to act as pharmacoperones or IL-1 receptor antagonists. ADMET information will be applied as a filter to rationally select compounds with druglike attributes (e.g., gut absorption, plasma stability, and blood-brain barrier permeability). The Core will also be responsible for synthesizing sufficient quantities (scaling-up) of the most promising second-generation compounds for further evaluation in cell-culture and in vivo experiments. All the Projects are expected to utilize Core D facilities for the evaluation of novel molecular entities as therapeutic agents having the ability to interact with the potential therapeutic priorties of each arm of the inflammation, proteinopathy, insulin-resistance triad.